Studies on the mechanisms of certain tryptophan reactions suggest that the indolenine tautomer should be the true substrate for some tryptophan-metabolizing enzymes. The first conclusive support for this concept is found in our demonstration that 2,3-dihydro-L- tryptophan and oxindolyl-L-alanine, analogs of the indolenine tautomer of tryptophan (tetrahedral carbon at C-3), are potent competitive inhibitors of tryptophan synthase and tryptophanase. Furthermore, the two enzymes show opposing specificity for the C- 3 diastereoisomers of 2,3-dihydro-L-tryptophan, suggesting that these enzymes catalyze their reactions via enantiomeric indolenine intermediates. Dioxindolyl-L-alanine (3R) is also an inhibitor of tryptophanase and matches the stereochemistry of (3R)-2,3-dihydro- L-tryptophan, which inhibits the same enzyme. 3-Azido-oxindolyl- L-alanine, a potential photoaffinity label for tryptophanase, has been prepared. Inhibition of the enzyme aldose reductase represents a new pharmacological approach toward the treatment of late-onset diabetic complications. These complications affect the eye, kidney, nervous system and circulation; they are thought to result from the hyperosmotic effects of high concentrations of sorbitol, in turn resulting from the reduction of the excess glucose symptomatic of diabetes. Our methods for the synthesis of inhibitors of tryptophan-metabolizing enzymes involve spirolactone intermediates which are fairly similar in overall structure to compounds now in clinical trials as aldose reductase inhibitors. The first series of compounds tested show the spirolactones to be active only at concentrations 100 times those of commercial inhibitors; however, the hydroxy-acids are ten times more active than the lactones. Replacement of the hydroxyl group by halogen and azido provides compounds which may act as affinity and photoaffinity labels.